Abstract
Backgroundα-Synuclein (α-Syn) is a protein implicated in the pathogenesis of Parkinson’s disease (PD). α-Syn has been shown to associate with membranes and bind acidic phospholipids. However, the physiological importance of these associations to the integrity of axons is not fully clear.MethodsBiochemical, immunohistochemical and ultrastructural analyses in cultured neurons, transgenic mouse brains, PD and control human brains.ResultsWe analyzed the ultrastructure of cross-sectioned axons localized to white matter tracts (WMTs), within the dorsal striatum of old and symptomatic α-Syn transgenic mouse brains. The analysis indicated a higher density of axons of thinner diameter. Our findings in cultured cortical neurons indicate a role for α-Syn in elongation of the main axon and its collaterals, resulting in enhanced axonal arborization. We show that α-Syn effect to enhance axonal outgrowth is mediated through its activity to regulate membrane levels of the acidic phosphatidylinositol 4,5-bisphosphate (PI4,5P2). Moreover, our findings link α-Syn- enhanced axonal growth with evidence for axonal injury. In relevance to disease mechanisms, we detect in human brains evidence for a higher degree of corticostriatal glutamatergic plasticity within WMTs at early stages of PD. However, at later PD stages, the respective WMTs in the caudate are degenerated with accumulation of Lewy pathology.ConclusionsOur results show that through regulating PI4,5P2 levels, α-Syn acts to elongate the main axon and collaterals, resulting in a higher density of axons in the striatal WMTs. Based on these results we suggest a role for α-Syn in compensating mechanisms, involving corticostriatal glutamatergic plasticity, taking place early in PD.
Highlights
Background αSynuclein (α-Syn) is a protein known for its critical roles in the cytopathology and genetics of Parkinson’s disease (PD) [1]
Using axonal and synaptic markers, we demonstrate a higher density of glutamatergic axons within corticostriatal white matter tracts (WMTs) and glutamatergic terminals, in the caudate of postmortem human brains affected with PD at early stages of the disease
Higher density of thinner axons in striatal WMTs of α-Syn tg mouse brains To investigate a potential role for α-Syn in axon integrity we analyzed the ultrastructure of cross-sectioned axons, localized within striatal WMTs, in coronal sections of A53T α-Syn tg and control mouse brains [20]
Summary
Background αSynuclein (α-Syn) is a protein known for its critical roles in the cytopathology and genetics of PD [1]. Neuroanatomy studies suggest that the length and caliber of axons, together with the degree of myelination, determine neuronal vulnerability to Lewy pathology [4,5,6]. Phylogenetic studies indicated a remarkable degree of αSyn sequence conservation throughout the evolution of vertebrate branches [7, 8] and identified two homologous proteins, β-Syn and γ-Syn. Analysis of the amino acid sequence of α-Syn protein indicated the occurrence of a 11mer repeats which make up a conserved apolipoproteinlike class-A2 helix [9]. Analysis of the amino acid sequence of α-Syn protein indicated the occurrence of a 11mer repeats which make up a conserved apolipoproteinlike class-A2 helix [9] These structural homologies provided the rationale for investigating the role of α-Syn associations with membrane lipids in its pathophysiology. Suggesting a possible involvement of α-Syn in the development of vertebrate’s brain complexity
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